The inflammation hypothesis of aging centers on the assertion that aging is the accumulation of damage, which results from chronic activity of immune response systems. Overproduction of pro-inflammatory cytokines has been linked to a number of chronic conditions common in older adults including cardiovascular disease, frailty, cognitive decline, dementia, and overall mortality. Evidence that pro-inflammatory cytokines contribute to hip fracture, however, does not exist despite animal and in-vitro data supporting such an association. Hip fractures are the most devastating consequence of osteoporosis. Preliminary analyses suggest that higher soluble cytokine receptor levels are associated with faster rates of bone loss and an increased risk of fracture. In the current application, we plan to test the inflammation of aging hypothesis as it relates to hip fracture in two distinct cohorts, the observational arm of The Women's Health Initiative (WHIOS) and the Study of Osteoporotic Fractures (SOF). The proposed study will consist of two prospective studies of biochemical predictors of hip fracture in the WHI-OS and SOF. In addition, we will measure cytokines, bone turnover markers and serum estradiol and vitamin D in 410 African American women enrolled in SOF and compare these levels to 700 Caucasian control women to identify the factors that contribute to ethnic differences in rates of bone loss. We hypothesize that increases in pro-inflammatory cytokines results in increased rates of bone turnover, loss of bone strength, faster rate of bone loss and an increased risk of hip fracture. Furthermore, estrogen deficiency leads to increases in pro-inflammatory cytokines and thus leads to hip fracture. Vitamin D insufficiency increases the risk of fracture by either increasing fall rates, reducing bone strength, or both. Our goal is to substantially improve our understanding of the paracrine and hormonal mediators that contribute to hip fracture in older women. Improved understanding of the biological mechanisms for these associations could lead to the development and testing of preventive intervention.